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The coordination sites of the Cu(I) and Cu(II) ions to the Aβ affect the production of Reactive Oxygen Species (ROS)

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Academic year: 2022

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My main research interest concerns the impact of metallic ions, mainly Cu and Zn on the amyloid cascade process linked to the etiology of Alzheimer's disease (AD). According to the amyloid cascade (Figure 1), metallic ions are involved in two deleterious events encountered in AD: the assembly of the amyloid-β peptides (Aβ) and the production of Reactive Oxygen Species by Cu- bound Aβ.

Fig. 1. The amyloid cascade process.

1-Metal binding to the amyloid- peptides. Seminal results are the determination by EPR, NMR and XAS of the Cu(II), Cu(I) and Zn(II) coordination spheres when bound to the human Aβ peptide and other biologically relevant Aβ peptides (truncated forms, murine variants, etc.) and of their affinity. For recent reviews, see: Coord. Chem. Rev. 2018, eicb 2018. More recently, we have been interested in the description of kinetics of metal exchange between Aβ and other biomolecules (Inorg Chem 2021).

2-ROS production. The coordination sites of the Cu(I) and Cu(II) ions to the Aβ affect the production of Reactive Oxygen Species (ROS). We have proposed that peculiar mechanism where the metal site goes through an intermediate geometry in which it becomes catalytic

(named “in-between state”) and we have recently deduced the environment of the copper center in the in-between state from complementary analytical methods (see Anal. Chem. 2018, Chem.

Sci. 2017 and PNAS 2010).

Fig. 2. Scheme of the in-between state (IBS) responsible for ROS production and of its equilibria with the resting (RS) in Cu(II) and Cu(I) redox state.

3-Self-assembly of amyloid-forming peptides. This process is at the core of several, so-called, amyloid diseases. The diseases are peptide-dependent and the deposits of -sheet-rich fibrils are localized at different places, e.g. in the pancreas in case of type 2 diabetes and in the brain in case of AD. Metal ions do modify the self-assembly process as do other synthetic and natural chaperones. Metal ions favor intermediates (oligomeric Aβ) and the chaperones disfavor such toxic species. Being able to reproduce the self-assembly process in vitro is challenging (FrontiersChem 2021). This is because the process is auto-catalytic due to secondary nucleation paths (Fig. 3). We have shown that metal ions do modulate the self-assembly paths (CEJ 2021) and we are currently investigating cross-talk between two amyloid-forming peptides in such

assembly process.

Fig. 3. Self-assembly of amyloid-forming peptides showing the nucleation-elongation mechanism and the secondary nucleation processes. Species present during the various assembly steps are shown in the three boxes, while the intermediates are regarded as the most neurotoxic species.

To progress in the deep understanding of peptide assembly, new probes and methods are needed and we are currently investigating molecules able to witness the formation of the early species of assembly.

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4-Therapeutic approaches. Because the interaction of Cu with the Aβ peptide is regarded as toxic, we have studied several proofs of concept regarding chelation and extraction out of Aβ. The most important one is the interference of Zn(II) in Cu chelation (DaltonTrans 2016, DaltonTrans 2017, CEJ 2018, InorgChem 2021) and removal from the Aβ peptide, Cu being considered as the target of choice due to its ability in ROS formation. We have also shown that Cu(I) (in addition to Cu(II)) should be considered in chelation therapy (Metallomics 2016,

Metallomics 2019, CEJ 2017, CEJ 2020), that kinetic aspects can also be important (CEJ 2017) and that inorganic prodrugs able to mask the toxicity of the ligand is an interesting strategy (CEJ 2018). Other strategies are currently under investigation.

Fig. 4. Scheme recapitulating some of the requirements of Cu-targeting molecules in the context of AD (From Inorg.Chem. 2019).

Another therapeutic approach relies on the fine-tuning of the self-assembly process to minimize the quantity of oligomers present during the process. We are studying the effects of polyanions such as POM, polyphosphates and biological chaperones (for e recent review, see ACS ChemNeurosc. 2019).

5-Detection approaches. The early detection is a key point for setting up therapeutic lines in due time.

We have a recently illustrate that point in case of Gd(III) complexes for further MRI studies (CEJ 2021).

We are currently investigating compounds able to probe selectivity different kinds of amyloids.

We are very thankful to the European Research Council (ERC StG-638712, aLzINK), ANR (PRC, DIVA PI:

E. Toth), CSC (granted to X. lin) for the funding of those projects.

Previous funding from USIAS Fellowship, France-Alzheimer and the Region Midi-Pyrénées are also warmly acknowledged.

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